Topical pharmaceutical gel composition of diclofenac sodium

ABSTRACT

Topical pharmaceutical gel compositions of diclofenac sodium are provided. The topical gel compositions contain at least about 10% w/w diclofenac sodium and are suitable for once-a-day topical application.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

The present invention is directed to novel topical pharmaceutical gelcompositions of diclofenac sodium. The topical compositions comprise atleast about 10% w/w of diclofenac sodium and are suitable for once-a-dayapplication. The invention is further directed to the use of saidcompositions for treating painful conditions, inflammations and/orrheumatic diseases or providing relief of the pain of osteoarthritis ofjoints amenable to topical treatment. Additionally, the presentinvention provides a method of manufacture of said composition.

(b) Description of the Related Art

Delivery of active agents across the skin or mucosal membrane isconvenient, pain-free, non-invasive and circumvents problems associatedwith the “first pass effect”. Such transdermal or topical drug deliveryis typically restricted to low molecular weight drugs and drugs withspecific lipophilic/hydrophilic balance able to penetrate the stratumcorneum.

Transdermal drug delivery systems enable chemical modification of thebarrier properties of the skin to effectively and efficiently permitpermeation thereof. Known drawbacks of transdermal delivery systems are,for example, the length of time needed for permeation, a frequent dosingregimen, and the volume size of a transdermal composition needed totransdermally deliver a sufficient therapeutic amount of the activeagent.

Diclofenac (2-(2,6-dichloranilino)phenylacetic acid) is a non-steroidalanti-inflammatory drug (NSAID) used to reduce inflammation and, as ananalgesic, to reduce pain. It is available in the sodium, potassium,epolamine and diethylamine salt forms in numerous dosage forms (oraltablet, oral syrup, topical gel, cataplasm, ophthalmic drop,suppository, etc.).

An example of a well-known transdermal diclofenac formulation isVoltaren® Gel 1% which comprises 1% diclofenac sodium. Voltaren® isindicated in the USA for the relief of the pain due to osteoarthritis ofjoints amenable to topical treatment, such as the knees and the hands.Up to 4 gm of Voltaren® gel can be applied to lower extremities(including the knees, the ankles, and the feet) 4 times daily so that upto not more than 16 gm daily of Voltaren® Gel 1% is applied to anysingle joint of the lower extremities. Up to 2 gm of Voltaren® Gel 1%can also be applied to the upper extremities (which include the elbows,the wrists and the hands) 4 times daily so that up to not more than 8 gmdaily of Voltaren® Gel 1% is applied to any single joint of the upperextremities. Overall, the total dose of Voltaren® Gel 1% should notexceed 32 gm per day over all affected joints. Neither the total amount(up to 32 gm per day) nor the frequency of application (4 times a day)is satisfactory from a patient perspective.

U.S. Pat. No. 7,335,379 discloses formulations for transdermal ortransmucosal administration of active agents, such as diclofenac,containing an alkanol, a polyalcohol, a monoalkyl ether of diethyleneglycol and a fatty alcohol with a fatty alcohol content of up to 2%.

U.S. Pat. No. 4,543,251 discloses an external gel formulation containing0.3 to 3% w/w of diclofenac sodium having good stability.

PCT Application Publication No. 2014009241 discloses diclofenac gelformulations containing 1% and 3% diclofenac sodium, C₂ to C₄ alkanol,monoalkyl ether of diethylene glycol and fatty alcohol.

U.S. Pat. No. 7,132,452 discloses topical formulations containing aNSAID, particularly diclofenac for alleviating pain/inflammationassociated with infection caused by herpes virus. The amount ofdiclofenac in the formulation can be 1-10% w/w of the entireformulation. The patent further discloses that the formulation providesa complete relief on application for seven days.

EP Pat. No. 1,890,687 discloses topical gel formulations of diclofenacsodium for relief of pain and inflammation. According to the patent theformulation may contain up to 10% w/w of diclofenac.

None of the prior art references disclose or suggest a topical gelformulation containing a high amount of diclofenac sodium, let alone thetherapeutic benefits of once-a-day topical application of diclofenacsodium.

There remains a need for topical compositions of diclofenac containingat least about 10% w/w of diclofenac sodium which are effective fortreating of painful conditions, inflammations, and specificallyproviding fast and effective treatment for alleviating symptoms relatingto pain of osteoarthritis of joints and requires only one-timeapplication in a day to achieve equal or more therapeutic benefits thanthose achieved by multiple applications of currently known 1% w/w or 3%w/w diclofenac gel formulations.

SUMMARY OF THE INVENTION

The present invention provides a topical pharmaceutical gel compositionconfigured for and suitable for once-a-day application of diclofenacsodium.

In one aspect, the invention provides a topically applicablepharmaceutical gel composition suitable for once-a-day application ofdiclofenac sodium comprising diclofenac sodium in an amount of at leastabout 10% w/w of the composition. Once-a-day application of saidpharmaceutical gel composition provides steady state blood levels ofdiclofenac that are comparable to steady state blood levels ofdiclofenac achieved with 4 times daily application of diclofenac sodium1% or 3% w/w topical gel.

In another aspect, once-a-day administration of said compositionprovides steady state blood levels of diclofenac in the range of about 5ng/ml to about 30 ng/ml.

In another aspect, once-a-day administration of said compositionprovides steady state blood C_(max) levels of diclofenac in the range ofabout 5 ng/ml to about 50 ng/ml.

In another aspect, once-a-day administration of said compositionprovides steady state blood C_(min) levels of diclofenac in the range ofabout 5 ng/ml to about 20 ng/ml.

In another aspect, once-a-day administration of said compositionprovides steady state AUC in the range of about 10 ng/ml*hr to about 100ng/ml*hr.

In another aspect, the topical pharmaceutical gel composition ofdiclofenac sodium comprises:

-   -   at least about 10% w/w of diclofenac sodium,    -   about 5-25% w/w of a glycol solvent,    -   about 1-6% w/w of at least one gelling agent,    -   about 0.01-0.75% w/w of at least one preservative,    -   about 0.01-1% w/w of at least one antioxidant,    -   about 1-10% w/w of salicylic acid ester,    -   about 0.05-1% w/w of menthol,    -   at least 50% w/w of water, and    -   at least one acidic and/or basic agent to adjust the pH of the        composition to 4-8.

In an embodiment, the amount of diclofenac sodium in the gel compositionof the invention is between about 10-14% w/w, such as about 10% w/w,about 12% w/w or about 14% w/w.

In another embodiment, the topical pharmaceutical gel composition isdevoid of either C₂ to C₄ alkanol, monoalkyl ether of diethylene glycol,or a fatty alcohol. Also provided is a topically applicable diclofenacsodium gel composition which is stable at room temperature. Methods oftreating painful conditions and inflammations or providing fast andeffective treatment for alleviating symptoms relating to the pain ofosteoarthritis of joints using these compositions are further providedby the invention.

In another aspect, the invention provides a topically appliedpharmaceutical gel composition intended for and suitable for once-a-dayapplication of diclofenac sodium. The topical pharmaceutical gelcomposition intended for and suitable for once-a-day topicaladministration consists of or consists essentially of: (a) about 10-15%w/w of diclofenac sodium; (b) about 5-25% w/w of a glycol solvent; (c)about 1-6% w/w of at least one gelling agent; (d) about 0.01-0.75% w/wof at least one preservative; (e) about 0.01-1% w/w of at least oneantioxidant; (f) about 1-10% w/w of salicylic acid ester; (g) about0.05-1% w/w of menthol; (h) at least 50% w/w of water; and (i) at leastone acidic and/or basic agent to adjust the pH of the composition to4-8.

Embodiments of this aspect may consist of or consist essentially ofabout (a) 10-15% w/w of diclofenac sodium; (b) about 5-25% w/w ofpropylene glycol as the glycol solvent; (c) about 1-6% w/w of carbomeras the gelling agent; (d) about 0.01-0.75% w/w of methyl paraben andpropyl paraben as the preservative; (e) about 0.01-1% w/w of at leastone edetate disodium as the antioxidant; (f) about 1-10% w/w of methylsalicylate as the salicylic acid ester; (g) about 0.05-1% w/w ofmenthol; (h) at least 50% w/w of water; and (i) at least one acidicand/or basic agent to adjust the pH of the composition to 4-8.

Another embodiment of this aspect may consist of or consist essentiallyof (a) about 10% w/w of diclofenac sodium; (b) about 10% w/w ofpropylene glycol as the glycol solvent; (c) about 3.5% w/w of carbomeras the gelling agent; (d) about 0.4% w/w of methyl paraben and propylparaben as the preservative; (e) about 0.17% w/w of at least one edetatedisodium as the antioxidant; (f) about 3% w/w of methyl salicylate asthe salicylate acid ester; (g) about 0.2% w/w of menthol; (h) at least50% w/w of water; and (i) at least one acidic and/or basic agent toadjust the pH of the composition to 4-8.

Another embodiment of this aspect may consist of or consist essentiallyof (a) about 14% w/w of diclofenac sodium; (b) about 20% w/w ofpropylene glycol as the glycol solvent; (c) about 2.5% w/w of carbomeras the gelling agent; (d) about 0.4% w/w of methyl paraben and propylparaben as the preservative; (e) about 0.17% w/w of at least one edetatedisodium as the antioxidant; (f) about 7% w/w of methyl salicylate asthe salicylate acid ester; (g) about 0.3% w/w of menthol; (h) at least50% w/w of water; and (i) at least one acidic and/or basic agent toadjust the pH of the composition to 4-8.

In these embodiments consisting of or consisting essentially ofparticular excipients to provide a composition suitable for once dailytopical administration, the topical pharmaceutical gel composition isdevoid of either C₂ to C₄ alkanol, monoalkyl ether of diethylene glycol,or fatty alcohol.

In another aspect, the invention provides a topical pharmaceutical gelcomposition suitable for once-a-day application of diclofenac sodiumcomprising a glycol solvent selected from the group consisting ofpropylene glycol, polyethylene glycol, ethylene glycol, butylene glycol,and hexalylene glycol. In one embodiment, the glycol solvent in the gelcomposition is propylene glycol. In further embodiments, the amount ofglycol solvent present in the gel composition is about 5-25% w/w.

In another aspect, the invention provides a topical pharmaceutical gelcomposition suitable for once-a-day application of diclofenac sodiumcomprising gelling agent selected from the group consisting ofhydroxypropyl cellulose and carbomers. In one embodiment, the gellingagent in the gel composition is carbomer. In further embodiments, theamount of gelling agent present in the gel composition is about 1-6%w/w.

In another aspect, the invention provides a topical pharmaceutical gelcomposition suitable for once-a-day application of diclofenac sodiumcomprising preservatives selected from the group consisting of methylparaben, propyl paraben, chlorocresol, thomersal, sorbic acid, potassiumsorbate and mixtures thereof. In one embodiment, the preservatives inthe gel composition are methyl paraben and propyl paraben. In furtherembodiments, the amount of preservatives present in the gel compositionis about 0.01-0.75% w/w.

In another aspect, the invention provides a topical pharmaceutical gelcomposition suitable for once-a-day application of diclofenac sodiumcomprising an antioxidant selected from the group consisting of edetatedisodium, sodium metabisulfite, propyl gallate, and edetate trisodium.In one embodiment, the antioxidant in the gel composition is edetatedisodium. In further embodiments, the amount of antioxidant present inthe gel composition is about 0.01-1% w/w.

In another aspect, the invention provides a topical pharmaceutical gelcomposition suitable for once-a-day application of diclofenac sodiumcomprising a salicylate ester selected from the group consisting ofmethyl salicylate, ethyl salicylate and glycol monosalicylate. In oneembodiment, the salicylate ester in the gel composition is methylsalicylate. In further embodiments, the amount of salicylate esterpresent in the gel composition is about 1-10% w/w.

In another aspect, the invention provides a topical pharmaceutical gelcomposition suitable for once-a-day application of diclofenac sodiumcomprising propylene glycol, carbomers, edetate disodium, methylsalicylate, menthol and sodium hydroxide.

In another aspect, the topical pharmaceutical gel of the invention isdevoid of either C₂ to C₂ to C₄ alkanol, monoalkyl ether of diethyleneglycol, or fatty alcohol.

In another aspect, the viscosity of the topical pharmaceutical gel ofthe invention is in the range of about 60,000 to 600,000 cps.

In another aspect, the invention provides a method for the manufactureof a topically applied diclofenac sodium gel composition, which processcomprises the steps of:

-   -   (a) dissolving diclofenac sodium, gelling agent, antioxidant and        preservative in water;    -   (b) dissolving preservative, salicylate ester and menthol in        glycol solvent;    -   (c) adding the solvent mixtures of steps (a) and (b) together        and mixing under high shear homogenization; and    -   (d) adjusting the pH of the mixture with a basic and/or acid        agent to a pH in the range of about 4 to 6.

In another aspect, the invention provides a method for the treatment ofpainful conditions, inflammations and/or rheumatic diseases comprisingtopically applying the gel compositions as described herein to a patientin need thereof.

Still other aspects and advantages of the invention will be apparentfrom the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides for a topical pharmaceutical gel compositionsuitable for once-a-day application of diclofenac sodium. Preferably,the composition contains, at least, a combination of a salicylate esterand menthol along with other components.

The invention addresses the need for topical gel formulations ofdiclofenac sodium which require only once-a-day application and providerelief which is comparable to that achieved by 4 times daily applicationof currently available diclofenac sodium 1% or 3% w/w formulations, suchas Voltaren® 1% Gel.

The invention, for example, provides topical gel formulation ofdiclofenac sodium containing about 10% w/w to about 15% w/w ofdiclofenac sodium. The inventors have observed that a particularformulation of diclofenac sodium requires only a single application in aday as compared to the frequent applications required for commerciallyavailable diclofenac gel formulations.

In one embodiment, once-a-day application of said pharmaceutical gelcomposition provides steady state blood levels of diclofenac that arecomparable to steady state blood levels of diclofenac achieved with 4times daily application of diclofenac sodium 1% or 3% w/w topical gel.

In one aspect, use of the term “comparable” with respect to achievingsteady state blood levels of diclofenac comparable to a 1% or 3% topicalgel means that the once daily application of the composition of theinvention is bioequivalent to the commercially available 1% or 3%topical gel topically applied four times daily. As well understood byone of skill in the art, bioequivalence has the term used by the US Foodand Drug Administration when comparing a test product to a referenceproduct.

In this aspect, the compositions are expected to be bioequivalent to atopically administered diclofenac sodium topical gel product with 1% to3% w/w diclofenac sodium that is topically administered four times perday. The in vivo bioavailability determinations for demonstratingbioequivalence can use plasma concentrations to assess maximum plasmaconcentration (C_(max)) and area under the curve (AUC).

Bioequivalence is established by comparing pharmacokinetic parameters,for example AUC and C_(max), of the present invention with the Voltaren®1% topical gel in healthy human subjects. The term “AUC” refers to thearea under the time/plasma concentration curve after the administrationof the diclofenac sodium topical dosage form to healthy human subjects.The term “C_(max)” refers to the maximum concentration of diclofenacsodium in the blood following the administration of the diclofenacsodium topical dosage form to healthy human subjects. Generally, to showbioequivalence, the 90% confidence interval of the AUC and C_(max)values of the test product should be within a range of 80% to 125% ofthe reference product (e.g., Voltaren® Gel 1%). The values of theexcipients can be varied as known by one of skill in the art to achievebioequivalence.

Once-a-day administration of said composition provides steady stateblood levels of diclofenac in the range of about 5 ng/ml to about 30ng/ml, steady state blood C_(max) levels of diclofenac in the range ofabout 5 ng/ml to about 50 ng/ml, steady state blood C_(min) levels ofdiclofenac in the range of about 5 ng/ml to about 20 ng/ml, and steadystate AUC in the range of about 10 ng/ml*hr to about 100 ng/ml*hr.

The inventors have further observed that a topical gel formulation ofdiclofenac sodium in accordance with the invention is storage stable ata temperature of about 40° C. and relative humidity of about 75% for aperiod of at least 3 months.

In one embodiment, the topical pharmaceutical gel composition suitablefor once-a-day application of diclofenac sodium comprises:

-   -   at least about 10% w/w of diclofenac sodium,    -   about 5-25% w/w of a glycol solvent,    -   about 1-6% w/w of at least one gelling agent,    -   about 0.01-0.75% w/w of at least one preservative,    -   about 0.01-1% w/w of at least one antioxidant,    -   about 1-10% w/w of salicylic acid ester,    -   about 0.05-1% w/w of menthol,    -   at least 50% w/w of water; and    -   at least one acidic and/or basic agent to adjust the pH of the        composition to 4-8.

In another embodiment, the amount of diclofenac sodium in the gelcomposition of the invention is about 10% w/w, about 12% w/w or about14% w/w.

In a further embodiment, the topical pharmaceutical gel composition isdevoid of either C₂ to C₄ alkanol, monoalkyl ether of diethylene glycolor fatty alcohol.

In an embodiment, the viscosity of the topical pharmaceutical gelcomposition is in the range of about 60,000 to 600,000 cps.

Suitable glycols include, by way of example and without limitation,propylene glycol, polyethylene glycol, ethylene glycol, butylene glycol,and hexalylene glycol. A preferred glycol is polyethylene glycol. Theglycol is preferably present in an amount of about 5-25% w/w.

Suitable gelling agents include, by way of example and withoutlimitation, carbomers, xanthan gum, acacia, tragacanth, sodium alginate,gelatin, modified starches, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, methyl cellulose, co-polymers formed between maleic anhydrideand methyl vinyl ether, methacrylate derivatives, polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, polyvinyl alcohol andmixtures thereof. A preferred gelling agent is carbomer. The gellingagent is preferably present in an amount of about 1-6% w/w.

Carbomers, in the context of the present invention, are defined as homo-or copolymers of acrylic acid that are cross-linked, e.g., with an allylether of pentaerythritol (allyl pentaerythritol) or an allyl ether ofsucrose (allyl sucrose). Copolymers are formed, e.g., with minor levelsof long chain alkyl acrylate co-monomers. Homopolymers are preferred.Non limiting examples of carbomers are carbomer 940, 971, 973, 974, 980,981, 941, 974, 934 and 910. Especially preferred are carbomers 980, 940,981, 941, 974, 934 and 910. Preferably, carbomers are present in anamount of about 1-6% w/w.

Suitable preservatives include, by way of example and withoutlimitation, methyl paraben, propyl paraben, chlorocresol, thomersal,sorbic acid, potassium sorbate and mixtures thereof. A preferredpreservative is the combination of methyl paraben and propyl paraben.The preservative(s) is preferably present in an amount of about0.01-0.75% w/w.

Suitable salicylic acid esters include, by way of example and withoutlimitation, methyl salicylate, ethyl salicylate and glycolmonosalicylate. A preferred salicylic acid ester is methyl salicylate.Salicylic acid ester is preferably present in an amount of about0.01-0.75% w/w. In another embodiment, the ratio of the amount ofdiclofenac sodium to salicylic acid ester is preferably in the range ofabout 1:0.1 to about 1:0.5.

Suitable antioxidants include, by way of example and without limitation,edetate disodium, sodium sulphite, sodium metabisulfite, propyl gallate,edetate trisodium, tocopherol derivatives, butylated hydroxyl toluene,butylated hydroxyl anisole, ascorbic acid, fumaric acid, malic acid, andcitric acid. A preferred antioxidant is edetate disodium. Theantioxidant is preferably present in an amount of about 0.01-1% w/w.

Suitable basic agents include, by way of example and without limitation,sodium hydroxide, potassium hydroxide and ammonia. A preferred basicagent is sodium hydroxide.

Suitable acidic agents include, by way of example and withoutlimitation, hydrochloric acid, acetic acid, lactic acid and citric acid.A preferred acidic agent is hydrochloric acid.

In one embodiment, the ratio of the amount of diclofenac sodium tomenthol is preferably in the range of about 1:0.01 to about 1:0.05.

The topical gel composition of the present invention further maycomprise at least one additional ingredient selected from bufferingagents, moisturizing agents, humectants, surfactants, neutralizingagents, chelating agents, and emollients.

In one embodiment, the topical pharmaceutical gel composition suitablefor once-a-day application of diclofenac sodium comprises:

-   -   about 10% w/w of diclofenac sodium,    -   about 10% w/w of propylene glycol,    -   about 3.5% w/w of carbomer,    -   about 0.4% w/w of methyl paraben and propyl paraben,    -   about 0.17% w/w of at least one edetate disodium,    -   about 3% w/w of methyl salicylate,    -   about 0.2% w/w of menthol,    -   at least 50% w/w of water, and    -   at least one acidic and/or basic agent to adjust the pH of the        composition to 4-8.

In one embodiment, the topical pharmaceutical gel composition suitablefor once-a-day application of diclofenac sodium comprises:

-   -   about 14% w/w of diclofenac sodium,    -   about 20% w/w of propylene glycol,    -   about 2.5% w/w of carbomer,    -   about 0.4% w/w of methyl paraben and propyl paraben,    -   about 0.17% w/w of at least one edetate disodium,    -   about 7% w/w of methyl salicylate,    -   about 0.3% w/w of menthol,    -   at least 50% w/w of water, and    -   at least one acidic and/or basic agent to adjust the pH of the        composition to 4-8.

The invention further provides a method for the manufacture of topicalgel formulation of diclofenac sodium. The method includes the followingsteps:

-   -   (a) dissolving diclofenac sodium, gelling agent, antioxidant and        preservative in water;    -   (b) dissolving preservative, salicylate ester and menthol in        glycol solvent;    -   (c) adding the solvent mixtures of steps (a) and (b) together        and mixing under high shear homogenization; and    -   (d) adjusting the pH of the mixture of step (c) with a basic        and/or acid agent to a pH in the range of about 4 to 6.

In one embodiment, the method for the manufacture of topical gelformulation of diclofenac sodium includes the following steps:

-   -   (a) dissolving diclofenac sodium, carbomer, edetate sodium and        methylparaben in water;    -   (b) dissolving propylparaben, methylsalicylate and menthol in        propylene glycol;    -   (c) adding the solvent mixtures of steps (a) and (b) together        and mixing under high shear homogenization; and    -   (d) adjusting the pH with sodium hydroxide and/or hydrochloric        acid to a pH in the range of about 4 to 6.

The topical gel formulation of diclofenac sodium of the invention may betopically applied to the affected areas of the skin to a patientsuffering from painful conditions, inflammations and/or rheumaticdiseases or for providing relief of the pain of osteoarthritis ofjoints.

Example 1 Diclofenac Sodium 10% w/w Topical Gel

TABLE 1 Sr. Quantity No. Ingredients % w/w 1 Diclofenac Sodium 10.00 2Carbomer 3.50 3 Edetate Disodium 0.17 4 Methyl paraben 0.30 5 Propylparaben 0.08 6 Propylene Glycol 10.00 7 Methyl Salicylate 3.00 8 Menthol0.10 9 Purified Water QS 10 Sodium Hydroxide/Hydrochloric Acid (to QSadjust pH to ~4-6)

Process:

Diclofenac sodium, carbomer, edetate sodium and methyl paraben weredissolved in water. Separately, propyl paraben, methyl salicylate andmenthol were dissolved in propylene glycol. The two solutions were addedtogether, mixed under high shear homogenization and the pH of themixture was adjusted to 4 to 6 with sodium hydroxide and/or hydrochloricacid. The viscosity of the gel measured was in the range of about 60,000to 600,000 cps.

Example 2 Diclofenac Sodium 12% w/w Topical Gel

TABLE 2 Sr. Quantity No. Ingredients % w/w 1 Diclofenac Sodium 12.00 2Carbomer 3.00 3 Edetate Disodium 0.17 4 Methyl paraben 0.30 5 Propylparaben 0.08 6 Propylene Glycol 15.00 7 Methyl Salicylate 5.00 8 Menthol0.20 9 Purified Water QS 10 Sodium Hydroxide/Hydrochloric Acid (to QSadjust pH to ~4-6)

Process:

The gel formulation was prepared by the process as per Example 1. The pHof the resulting mixture was adjusted to 4 to 6 with sodium hydroxideand/or hydrochloric acid and the viscosity of the gel was measured andfound to be in the range of about 60,000 to 600,000 cps.

Example 3 Diclofenac Sodium 14% w/w Topical Gel

TABLE 3 Sr. Quantity No. Ingredients % w/w 1 Diclofenac Sodium 14.00 2Carbomer 2.50 3 Edetate Disodium 0.17 4 Methyl paraben 0.30 5 Propylparaben 0.08 6 Propylene Glycol 20.00 7 Methyl Salicylate 7.00 8 Menthol0.3 9 Ethyl Alcohol 5.0 10 Purified Water QS 11 SodiumHydroxide/Hydrochloric Acid (to QS adjust pH to ~4-6)

Process:

Diclofenac sodium, carbomer, edetate sodium and methyl paraben weredissolved in water. Separately, propyl paraben, methyl salicylate andmenthol were dissolved in ethyl alcohol. The remainder of theformulation was prepared by the process as per Example 1. The pH of themixture was adjusted to 4 to 6 with sodium hydroxide and/or hydrochloricacid and the viscosity of the gel was measured to be in the range ofabout 60,000 to 600,000 cps.

What is claimed is:
 1. A topical pharmaceutical gel composition ofdiclofenac comprising: at least about 10% w/w of diclofenac sodium;about 5-25% w/w of a glycol solvent; about 1-6% w/w of at least onegelling agent; about 0.01-0.75% w/w of at least one preservative; about0.01-1% w/w of at least one antioxidant; about 1-10% w/w of a salicylicacid ester; about 0.05-1% w/w of menthol; at least 50% w/w of water; andat least one acidic and/or basic agent to adjust the pH of thecomposition to 4-8, wherein the ratio of the amount of diclofenac sodiumto the amount of the salicylic acid ester is about 1:0.1 to about 1:0.5and/or the ratio of the amount of diclofenac sodium to the amount ofmenthol is about 1:0.01 to about 1:0.05.
 2. The topical gel compositionof claim 1, wherein the glycol solvent is selected from the groupconsisting of propylene glycol, polyethylene glycol, ethylene glycol,butylene glycol, and hexylene glycol.
 3. The topical gel composition ofclaim 2, wherein the glycol solvent is propylene glycol.
 4. The topicalgel composition of claim 1, wherein the at least one gelling agent isselected from the group consisting of carbomers, xanthan gum, acacia,tragacanth, sodium alginate, gelatin, modified starches, hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,hydroxypropyl methylcellulose phthalate, methyl cellulose, co-polymersformed between maleic anhydride and methyl vinyl ether, methacrylatederivatives, polyethylene oxides, polyoxyethylene-polyoxypropylenecopolymers, polyvinyl alcohol and mixtures thereof.
 5. The topical gelcomposition of claim 4, wherein the gelling agent is carbomer.
 6. Thetopical gel composition of claim 1, wherein the at least onepreservative is selected from the group consisting of methyl paraben,propyl paraben, chlorocresol, thiomersal, sorbic acid, potassium sorbateand mixtures thereof.
 7. The topical gel composition of claim 1, whereinthe at least one antioxidant is selected from the group consisting ofedetate disodium, sodium sulphite, sodium metabisulfite, propyl gallate,edetate trisodium, tocopherol derivatives, butylated hydroxyl toluene,butylated hydroxyl anisole, ascorbic acid, fumaric acid, malic acid, andcitric acid.
 8. The topical gel composition of claim 1, wherein theantioxidant is edetate disodium.
 9. The topical gel composition of claim1, wherein the salicylic acid ester is selected from the groupconsisting of methyl salicylate, ethyl salicylate and glycolmonosalicylate.
 10. The topical gel composition of claim 1, wherein theacidic and basic agents are selected from the group consisting of sodiumhydroxide, potassium hydroxide, ammonia, hydrochloric acid, acetic acid,lactic acid and citric acid.
 11. A topical pharmaceutical gelcomposition suitable for once-a-day application of diclofenaccomprising: at least about 10% w/w of diclofenac sodium; about 5-25% w/wof a glycol solvent; about 1-6% w/w of at least one gelling agent; about0.01-0.75% w/w of at least one preservative; about 0.01-1% w/w of atleast one antioxidant; about 1-10% w/w of a salicylic acid ester; about0.05-1% w/w of menthol; at least 50% w/w of water; and at least oneacidic and/or basic agent to adjust the pH of the composition to 4-8,wherein the ratio of the amount of diclofenac sodium to the amount ofthe salicylic acid ester is about 1:0.1 to about 1:0.5.
 12. A topicalpharmaceutical gel composition suitable for once-a-day application ofdiclofenac comprising: at least about 10% w/w of diclofenac sodium;about 5-25% w/w of a glycol solvent; about 1-6% w/w of at least onegelling agent; about 0.01-0.75% w/w of at least one preservative; about0.01-1% w/w of at least one antioxidant; about 1-10% w/w of a salicylicacid ester; about 0.05-1% w/w of menthol; at least 50% w/w of water; andat least one acidic and/or basic agent to adjust the pH of thecomposition to 4-8, wherein the ratio of the amount of diclofenac sodiumto the amount of menthol is about 1:0.01 to about 1:0.05.
 13. Thetopical gel composition of claim 1, wherein the gel is devoid of eitherC₂ to C₄ alkanol, monoalkyl ether of diethylene glycol, or fattyalcohol.
 14. The topical gel composition of claim 1, wherein once-a-daytopical application of said gel composition provides steady state bloodlevels of diclofenac that are comparable to steady state blood levels ofdiclofenac achieved with 4 times daily topical application of diclofenacsodium 1% or 3% topical gel.
 15. A method for the treatment of painfulconditions, inflammations and/or rheumatic diseases comprising topicallyapplying the gel composition of claim 1 to a patient in need thereof.16. The method of claim 15, wherein once-a-day topical application ofthe gel composition provides steady state blood levels of diclofenacthat are comparable to steady state blood levels of diclofenac achievedwith 4 times daily topical application of diclofenac sodium 1% or 3%topical gel.
 17. A topical pharmaceutical gel composition intended forand suitable for once-a-day application of diclofenac consisting of:about 10-15% w/w of diclofenac sodium; about 5-25% w/w of a glycolsolvent; about 1-6% w/w of at least one gelling agent; about 0.01-0.75%w/w of at least one preservative; about 0.01-1% w/w of at least oneantioxidant; about 1-10% w/w of salicylic acid ester; about 0.05-1% w/wof menthol; at least 50% w/w of water; and at least one acidic and/orbasic agent to adjust the pH of the composition to 4-8, wherein theratio of the amount of diclofenac sodium to the amount of the salicylicacid ester is about 1:0.1 to about 1:0.5 and/or the ratio of the amountof diclofenac sodium to the amount of menthol is about 1:0.01 to about1:0.05.
 18. The topical pharmaceutical gel composition of claim 17consisting of: about 10-15% w/w of diclofenac sodium; about 5-25% w/w ofpropylene glycol as the glycol solvent; about 1-6% w/w of carbomer asthe gelling agent; about 0.01-0.75% w/w of methyl paraben and propylparaben as the preservative; about 0.01-1% w/w of at least one edetatedisodium as the antioxidant; about 1-10% w/w of methyl salicylate as thesalicylic acid ester; about 0.05-1% w/w of menthol; at least 50% w/w ofwater; and at least one acidic and/or basic agent to adjust the pH ofthe composition to 4-8.
 19. The topical pharmaceutical gel compositionof claim 18 consisting of: about 10% w/w of diclofenac sodium; about 10%w/w of propylene glycol as the glycol solvent; about 3.5% w/w ofcarbomer as the gelling agent; about 0.4% w/w of methyl paraben andpropyl paraben as the preservative; about 0.17% w/w of at least oneedetate disodium as the antioxidant; about 3% w/w of methyl salicylateas the salicylate acid ester; about 0.2% w/w of menthol; at least 50%w/w of water; and at least one acidic and/or basic agent to adjust thepH of the composition to 4-8.
 20. The topical pharmaceutical gelcomposition of claim 18 consisting of: about 14% w/w of diclofenacsodium; about 20% w/w of propylene glycol as the glycol solvent; about2.5% w/w of carbomer as the gelling agent; about 0.4% w/w of methylparaben and propyl paraben as the preservative; about 0.17% w/w of atleast one edetate disodium as the antioxidant; about 7% w/w of methylsalicylate as the salicylate acid ester; about 0.3% w/w of menthol; atleast 50% w/w of water; and at least one acidic and/or basic agent toadjust the pH of the composition to 4-8.